CN104910209A - Tenofovir preparation method - Google Patents
Tenofovir preparation method Download PDFInfo
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- CN104910209A CN104910209A CN201410088446.4A CN201410088446A CN104910209A CN 104910209 A CN104910209 A CN 104910209A CN 201410088446 A CN201410088446 A CN 201410088446A CN 104910209 A CN104910209 A CN 104910209A
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- tenofovir
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- 229960004556 tenofovir Drugs 0.000 title claims abstract description 30
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 12
- RUOJZAUFBMNUDX-GSVOUGTGSA-N (4r)-4-methyl-1,3-dioxolan-2-one Chemical compound C[C@@H]1COC(=O)O1 RUOJZAUFBMNUDX-GSVOUGTGSA-N 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 235000013343 vitamin Nutrition 0.000 claims description 9
- 239000011782 vitamin Substances 0.000 claims description 9
- 229940088594 vitamin Drugs 0.000 claims description 9
- 229930003231 vitamin Natural products 0.000 claims description 9
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- YACKEPLHDIMKIO-UHFFFAOYSA-L methylphosphonate(2-) Chemical compound CP([O-])([O-])=O YACKEPLHDIMKIO-UHFFFAOYSA-L 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- ORPJQHHQRCLVIC-UHFFFAOYSA-N magnesium;propan-2-olate Chemical compound CC(C)O[Mg]OC(C)C ORPJQHHQRCLVIC-UHFFFAOYSA-N 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 7
- 235000015320 potassium carbonate Nutrition 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- -1 methane amide Chemical class 0.000 claims description 3
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- ZSUUCLLIOSUIFH-UHFFFAOYSA-N n,n-di(propan-2-yl)acetamide Chemical compound CC(C)N(C(C)C)C(C)=O ZSUUCLLIOSUIFH-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 2
- LVOASXNJWPROPP-UHFFFAOYSA-N (4-methylphenyl)sulfonyloxymethylphosphonic acid Chemical compound CC1=CC=C(S(=O)(=O)OCP(O)(O)=O)C=C1 LVOASXNJWPROPP-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 238000009413 insulation Methods 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 238000010792 warming Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- MZSBWBNMVOPWIU-UHFFFAOYSA-N C(C)OP(OCC)(O)C.[O] Chemical compound C(C)OP(OCC)(O)C.[O] MZSBWBNMVOPWIU-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940124977 antiviral medication Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003168 generic drug Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a tenofovir preparation method. The method comprises reactions with equations shown in the specification; and in the equations, A is a C1-C4 alkylcarbonyl group or an aryl-substituted C1-C4 alkylcarbonyl group, B is H, a C1-C4 alkylcarbonyl group or an aryl-substituted C1-C4 alkylcarbonyl group, R is a C1-C3 alkyl group or a phenyl group, R' is H, a C1-C3 alkyl group or a phenyl group, a reaction a is characterized in that a compound of formula III reacts with (R)-propylene carbonate and dialkyl (tosyloxy)methylphosphonate to generate an intermediate II, and a reaction b is characterized in that the intermediate II is hydrolyzed under the action of an inorganic acid to remove a protection group in order to obtain tenofovir. The method can realize synthesis of highly pure tenofovir in low cost and high yield by using cheap and easily available raw materials through simple operation under mild reaction conditions, has the advantages of energy saving and environmental protection, is suitable for large scale production, and has significant values for realizing the industrial production of tenofovir.
Description
Technical field
The present invention relates to a kind of method preparing tenofovir, belong to field of pharmaceutical chemistry technology.
Background technology
Tenofovir is used for the treatment of the nucleotide analog of HIV-1 infection by FDA approval as first, its importance is admitted by the World Health Organization, and is proposed as a line antiviral medication.Due to the material impact of this medicine, India accepts the request of Indian generic drug manufacturer Cipla in September, 2009, refuses to carry out patent protection to tenofovir, to ensure that this medicine can more easily by low income country be accepted.Its chemical structural formula is as follows:
Meanwhile, because tenofovir also has outstanding effect in antiviral therapy field, except being applied to anti-AIDS treatment, hepatitis B virus resisting also shows good therapeutic action.
Periodical literature 2010 deliver: Organic Process Research & Development, 2010,14,1194 ~ 1201 by summing up the existing production technique of tenofovir, and to corresponding links carry out careful compare with optimization after propose the synthesis technique that is applicable to suitability for industrialized production:
This technique has very strong production safety and yield stability, but still there is following open defect:
1, in the reaction generating intermediate 2, when magnesium salts mixture transforms to tenofovir, must by magnesium salts mixture via ethyl acetate force analyse after separate from system, due to the easy moisture absorption of this magnesium salts mixture and adsorption production, in actual treatment, operational requirement is high, and very loaded down with trivial details;
2, intermediate 2 is due to two ethyls that will dissociate, and must use harsh condition of dissociating;
3, from cost, owing to using greatly excessive trimethyl silane and Sodium Bromide, be that production cost or environmental protection all exist serious defect.
Following a kind of improvement route is disclosed in Chinese patent CN102219805:
Although this technique overcomes some defects of above-mentioned paper route, owing to adopting highly basic if sodium hydroxide was 120 DEG C of back flow reaction 22 hours when it prepares intermediate 1, this reaction conditions is violent, consuming time longer, and large production is difficult to control.
Disclosing a kind of in Chinese patent CN201210552918.8 is the method that raw material one kettle way prepares tenofovir with VITAMIN B4, and reaction formula is as follows:
Although this process simplify technological operation, reduce cost, be conducive to suitability for industrialized production, but the method is the same with the preparation technology about tenofovir in prior art: be all take VITAMIN B4 as starting raw material, and VITAMIN B4 and the reaction of R-propylene carbonate can produce the by product that 7-position replaces: (R)-7-(2-hydroxypropyl) VITAMIN B4, generally this by product is more than 7%; And change the content that catalyzer, solvent or temperature all have no idea to reduce this by product, and this isomer also can participate in subsequent reactions, thus cause a difficult problem for subsequent disposal and the raising of cost, so that still can not meet the demand of preparation of industrialization high purity tenofovir ideally.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of method preparing tenofovir is provided, to meet the demand of preparation of industrialization high purity tenofovir ideally.
For achieving the above object, the technical solution used in the present invention is as follows:
Prepare a method for tenofovir, comprise following reaction:
, wherein:
C1 ~ C4 alkyl-carbonyl that A is C1 ~ C4 alkyl-carbonyl or is replaced by aryl; C1 ~ C4 alkyl-carbonyl that B is H, C1 ~ C4 alkyl-carbonyl or is replaced by aryl; R is C1 ~ C3 alkyl or phenyl; R ' is H, C1 ~ C3 alkyl or phenyl;
Reaction a makes formula III compound react with (R)-propylene carbonate and tolysulfonyl oxygen dialkyl methyl phosphonate to generate intermediate II;
Reaction b makes intermediate II be hydrolyzed deprotection base under mineral acid effect, obtains Compound I (tenofovir).
As a kind of preferred version, formula III compound is prepared by VITAMIN B4 and acylating reagent generation acylation reaction and is obtained.
As a kind of preferred version, reaction a comprises following operation: be dissolved in organic solvent by formula III compound, inorganic weak bases, R-propylene carbonate, react at 90 ~ 130 DEG C after 2 ~ 10 hours and be down to room temperature, add highly basic, react 0.5 ~ 2 hour at 20 ~ 50 DEG C, then add tolysulfonyl oxygen dialkyl methyl phosphonate, reaction is continued 4 ~ 10 hours at 20 ~ 50 DEG C, be down to room temperature, concentrating under reduced pressure reaction system, obtains intermediate II.
As further preferred version, described inorganic weak bases is salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate; Described highly basic is selected from magnesium isopropoxide, tert-butyl alcohol magnesium or potassium tert.-butoxide; Described organic solvent is selected from least one in methane amide, DMF, ethanamide, N-methylacetamide, N, N-di-isopropyl ethanamide, N-Methyl pyrrolidone, N-methylpiperidone.
As further preferred version, the mol ratio of described inorganic weak bases and formula III compound is 1:1 ~ 10:1; The mol ratio of described highly basic and formula III compound is 1:1 ~ 10:1; Described tolysulfonyl oxygen dialkyl methyl phosphonate and the mol ratio of formula III compound are 1:1 ~ 10:1.
As a kind of preferred version, reaction b comprises following operation: in intermediate II, add mineral acid, reacts after 3 ~ 6 hours and is cooled to room temperature, continue reaction 1 ~ 2 hour, then through aftertreatment, obtain tenofovir at 90 ~ 110 DEG C.
As further preferred version, described aftertreatment comprises following operation: filtering reacting liquid, collects filtrate, leaves standstill make crystallization after regulating pH=2 ~ 3 of filtrate at 0 ~ 20 DEG C; Suction filtration, collects crystal, carries out washing and vacuum-drying.
As further preferred version, described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or sulfuric acid.
As further preferred version, described mineral acid and the mol ratio of intermediate II are 1:1 ~ 15:1.
Tolysulfonyl oxygen dialkyl methyl phosphonate involved in the present invention is commercially available to be obtained.
The present invention compared with prior art, has following unusual effect:
1) the present invention adopts VITAMIN B4 cheap and easy to get to be raw material; not only greatly reduce cost; and by the protection to 7-bit amino; thus effectively prevent the by product of 7-position of the prior art replacement: the generation of (R)-7-(2-hydroxypropyl) VITAMIN B4, is conducive to the raising of follow-up yield and product purity.
2) the present invention adopts weak base to react in formula III compound and propylene carbonate ester react, not only there is reaction conditions gentleness, simple operation and other advantages, key ensure that the protecting group of 7-bit amino not easily removes, and further avoid the by product that 7-position replaces: the generation of (R)-7-(2-hydroxypropyl) VITAMIN B4; And follow-up react with tolysulfonyl oxygen dialkyl methyl phosphonate in adopt highly basic, the protecting group one pot of 7-bit amino is removed, thus substantially reduces the reaction times, be more suitable for suitability for industrialized production.
In a word; utilize the inventive method can realize utilizing the object of raw material cheap and easy to get, simple operations, gentle reaction conditions, low cost, high yield synthesis of high purity (HPLC purity reaches more than 98%) tenofovir; energy-conserving and environment-protective; be applicable to large-scale production, to the suitability for industrialized production realizing tenofovir, there is significance and be worth.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely.
Embodiment 1:
As shown in Scheme 1, by compound III (17.4g, 0.13mol), salt of wormwood (21.5g, 0.15mol), R-propylene carbonate (15.8g, 0.15mol) be dissolved in 50mL DMF, be heated to 90 ~ 125 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, under argon shield, add magnesium isopropoxide (15.7g, 0.14mol), be warming up to 30 ~ 45 DEG C of insulation reaction 0.5 ~ 1 hour; Drip tolysulfonyl oxygen methyl-phosphorous acid diethyl ester (45.9g, 0.15mol) again, continue insulation reaction 4 ~ 6 hours at 30 ~ 45 DEG C; Finally system is down to room temperature, concentrating under reduced pressure reaction system, obtains intermediate II (oily matter for thickness).
In intermediate II, add 124g concentrated hydrochloric acid, be warming up to 90 ~ 110 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, at room temperature continue reaction 1 ~ 2 hour, suction filtration, the diluted hydrochloric acid aqueous solution of filter cake 150mL5wt% washs 2 times, and filtrate regulates pH=2 ~ 3 with sodium hydroxide solution, at room temperature leaves standstill crystallization and spends the night, then be cooled to 0 ~ 3 DEG C, make continuation crystallization 3 hours; Suction filtration, filter cake use successively 30mL water washing once, the mixed solvent (V/V=1:1) of 50mL water and acetone washs 2 times, 50mL washing with acetone 1 time; In 45 DEG C of vacuum-dryings, obtain Compound I: tenofovir 40.3g, total molar yield is 74.0%, HPLC purity is 98.2%.
Embodiment 2:
As shown in Scheme 2, by compound III (17.4g, 0.13mol), salt of wormwood (21.5g, 0.15mol), R-propylene carbonate (15.8g, 0.15mol) be dissolved in 50mL DMF, be heated to 90 ~ 125 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, under argon shield, add magnesium isopropoxide (15.7g, 0.14mol), be warming up to 30 ~ 45 DEG C of insulation reaction 0.5 ~ 1 hour; Drip tolysulfonyl oxygen dimethyl methyl phosphonate (44.1g, 0.15mol) again, continue insulation reaction 4 ~ 6 hours at 30 ~ 45 DEG C; Finally system is down to room temperature, concentrating under reduced pressure reaction system, obtains intermediate II (oily matter for thickness).
In intermediate II, add 96g concentrated hydrochloric acid, be warming up to 90 ~ 110 DEG C, insulation reaction 3 ~ 6 hours; Then be down to room temperature, at room temperature continue reaction 1 ~ 2 hour, suction filtration, the diluted hydrochloric acid aqueous solution of filter cake 150mL5wt% washs 2 times, and filtrate regulates pH=2 ~ 3 with sodium hydroxide solution, at room temperature leaves standstill crystallization and spends the night, then be cooled to 0 ~ 3 DEG C, make continuation crystallization 3 hours; Suction filtration, filter cake use successively 30mL water washing once, the mixed solvent (V/V=1:1) of 50mL water and acetone washs 2 times, 50mL washing with acetone 1 time; In 45 DEG C of vacuum-dryings, obtain Compound I: tenofovir 21.9g, total molar yield is 76.5%, HPLC purity is 98.2%.
Embodiment 3:
As shown in Scheme 3, by compound III (17.4g, 0.13mol), salt of wormwood (21.5g, 0.15mol), R-propylene carbonate (15.8g, 0.15mol) be dissolved in 50mL DMF, be heated to 90 ~ 125 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, under argon shield, add magnesium isopropoxide (15.7g, 0.14mol), be warming up to 30 ~ 45 DEG C of insulation reaction 0.5 ~ 1 hour; Drip tolysulfonyl oxygen methyl-phosphorous acid diethyl ester (45.9g, 0.15mol) again, continue insulation reaction 4 ~ 6 hours at 30 ~ 45 DEG C; Finally system is down to room temperature, adds dilute hydrochloric acid 50mL and stir 3 hours, concentrating under reduced pressure reaction system, obtain intermediate II (oily matter for thickness).
In intermediate II, add 96g concentrated hydrochloric acid, be warming up to 90 ~ 110 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, at room temperature continue reaction 1 ~ 2 hour, suction filtration, the diluted hydrochloric acid aqueous solution of filter cake 150mL5wt% washs 2 times, and filtrate regulates pH=2 ~ 3 with sodium hydroxide solution, at room temperature leaves standstill crystallization and spends the night, then be cooled to 0 ~ 3 DEG C, make continuation crystallization 3 hours; Suction filtration, filter cake use successively 30mL water washing once, the mixed solvent (V/V=1:1) of 50mL water and acetone washs 2 times, 50mL washing with acetone 1 time; In 45 DEG C of vacuum-dryings, obtain Compound I: tenofovir 22.3g, total molar yield is 78.1%, HPLC purity is 98.6%.
Embodiment 4
As shown in Scheme 4, by compound III (17.4g, 0.13mol), salt of wormwood (21.5g, 0.15mol), R-propylene carbonate (15.8g, 0.15mol) be dissolved in 50mL DMF, be heated to 90 ~ 125 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, under argon shield, add magnesium isopropoxide (15.7g, 0.14mol), be warming up to 30 ~ 45 DEG C of insulation reaction 0.5 ~ 1 hour; Drip tolysulfonyl oxygen methyl-phosphorous acid diethyl ester (45.9g, 0.15mol) again, continue insulation reaction 4 ~ 6 hours at 30 ~ 45 DEG C; Finally system is down to room temperature, add dilute hydrochloric acid and regulate pH to be 3 ~ 4, concentrating under reduced pressure reaction system, obtains intermediate compound I (oily matter for thickness).
In intermediate II, add 96g concentrated hydrochloric acid, be warming up to 90 ~ 110 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, at room temperature continue reaction 1 ~ 2 hour, suction filtration, the diluted hydrochloric acid aqueous solution of filter cake 150mL5wt% washs 2 times, and filtrate regulates pH=2 ~ 3 with sodium hydroxide solution, at room temperature leaves standstill crystallization and spends the night, then be cooled to 0 ~ 3 DEG C, make continuation crystallization 3 hours; Suction filtration, filter cake use successively 30mL water washing once, the mixed solvent (V/V=1:1) of 50mL water and acetone washs 2 times, 50mL washing with acetone 1 time; In 45 DEG C of vacuum-dryings, obtain Compound I: tenofovir 21.9g, total molar yield is 76.8%, HPLC purity is 98.7%.
Embodiment 5
As shown in Scheme 5, by compound III (17.4g, 0.13mol), salt of wormwood (21.5g, 0.15mol), R-propylene carbonate (15.8g, 0.15mol) be dissolved in 50mL DMF, be heated to 90 ~ 125 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, under argon shield, add magnesium isopropoxide (15.7g, 0.14mol), be warming up to 30 ~ 45 DEG C of insulation reaction 0.5 ~ 1 hour; Drip tolysulfonyl oxygen methyl-phosphorous acid diethyl ester (45.9g, 0.15mol) again, continue insulation reaction 4 ~ 6 hours at 30 ~ 45 DEG C; Finally system is down to room temperature, adds sodium hydroxide (8g, 0.2mol) and stir 3 hours, concentrating under reduced pressure reaction system, obtain intermediate II (oily matter for thickness).
In intermediate II, add 96g concentrated hydrochloric acid, be warming up to 90 ~ 110 DEG C of insulation reaction 3 ~ 6 hours; Then be down to room temperature, at room temperature continue reaction 1 ~ 2 hour, suction filtration, the diluted hydrochloric acid aqueous solution of filter cake 150mL5wt% washs 2 times, and filtrate regulates pH=2 ~ 3 with sodium hydroxide solution, at room temperature leaves standstill crystallization and spends the night, then be cooled to 0 ~ 3 DEG C, make continuation crystallization 3 hours; Suction filtration, filter cake use successively 30mL water washing once, the mixed solvent (V/V=1:1) of 50mL water and acetone washs 2 times, 50mL washing with acetone 1 time; In 45 DEG C of vacuum-dryings, obtain Compound I: tenofovir 21.8g, total molar yield is 76.2%, HPLC purity is 98.6%.
Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (9)
1. prepare a method for tenofovir, it is characterized in that, comprise following reaction:
, wherein:
C1 ~ C4 alkyl-carbonyl that A is C1 ~ C4 alkyl-carbonyl or is replaced by aryl; C1 ~ C4 alkyl-carbonyl that B is H, C1 ~ C4 alkyl-carbonyl or is replaced by aryl; R is C1 ~ C3 alkyl or phenyl; R ' is H, C1 ~ C3 alkyl or phenyl;
Reaction a makes formula III compound react with (R)-propylene carbonate and tolysulfonyl oxygen dialkyl methyl phosphonate to generate intermediate II;
Reaction b makes intermediate II be hydrolyzed deprotection base under mineral acid effect, obtains Compound I (tenofovir).
2. the method for claim 1, is characterized in that: formula III compound is prepared by VITAMIN B4 and acylating reagent generation acylation reaction and obtained.
3. the method for claim 1, it is characterized in that, reaction a comprises following operation: be dissolved in organic solvent by formula III compound, inorganic weak bases, R-propylene carbonate, reacts after 2 ~ 10 hours and is down to room temperature, add highly basic at 90 ~ 130 DEG C, react 0.5 ~ 2 hour at 20 ~ 50 DEG C, then add tolysulfonyl oxygen dialkyl methyl phosphonate, at 20 ~ 50 DEG C, continue reaction 4 ~ 10 hours, be down to room temperature, concentrating under reduced pressure reaction system, obtains intermediate II.
4. method as claimed in claim 3, is characterized in that: described inorganic weak bases is salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate; Described highly basic is selected from magnesium isopropoxide, tert-butyl alcohol magnesium or potassium tert.-butoxide; Described organic solvent is selected from least one in methane amide, DMF, ethanamide, N-methylacetamide, N, N-di-isopropyl ethanamide, N-Methyl pyrrolidone, N-methylpiperidone.
5. method as claimed in claim 3, is characterized in that: the mol ratio of described inorganic weak bases and formula III compound is 1:1 ~ 10:1; The mol ratio of described highly basic and formula III compound is 1:1 ~ 10:1; Described tolysulfonyl oxygen dialkyl methyl phosphonate and the mol ratio of formula III compound are 1:1 ~ 10:1.
6. the method for claim 1, it is characterized in that: reaction b comprises following operation: in intermediate II, add mineral acid, react at 90 ~ 110 DEG C after 3 ~ 6 hours and be cooled to room temperature, continue reaction 1 ~ 2 hour, then through aftertreatment, tenofovir is obtained.
7. method as claimed in claim 6, it is characterized in that, described aftertreatment comprises following operation: filtering reacting liquid, collects filtrate, leaves standstill make crystallization after regulating pH=2 ~ 3 of filtrate at 0 ~ 20 DEG C; Suction filtration, collects crystal, carries out washing and vacuum-drying.
8. method as claimed in claim 6, is characterized in that: described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or sulfuric acid.
9. method as claimed in claim 6, is characterized in that: described mineral acid and the mol ratio of intermediate II are 1:1 ~ 15:1.
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Cited By (2)
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| CN107021984A (en) * | 2017-04-28 | 2017-08-08 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
| CN111205326A (en) * | 2020-02-13 | 2020-05-29 | 南京道尔医药科技有限公司 | Green and environment-friendly preparation method of tenofovir |
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| CN111205326A (en) * | 2020-02-13 | 2020-05-29 | 南京道尔医药科技有限公司 | Green and environment-friendly preparation method of tenofovir |
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